Primary symptomatology in Alzheimer~s disease (AD) has been attributed to a presynaptic cholinergic deficit, based mainly on post- mortem examination of the brain at the end stages of the illness. Pharmacologic enhancement of the cholinergic system has not been consistently efficacious and does not stop disease progression. Animal and human models of AD based on inducted cholinergic hypofunction only mimic some aspects of symptomatology in AD. More recent neuropathologic studies have reported deficits in other neurotransmitter systems (e.g. dopamine, serotonin, norepinephrine). As an integration of the present knowledge concerning the neurochemistry of AD and the observation that neurotransmitter systems function synergistically, not in isolation, the proposed studies will test the novel hypothesis that the cognitive and behavioral symptomatology in AD represents a failure of acetylcholine to modulate other functionally-linked neurotransmitters, and that these deficits occur prior to the clinical diagnosis of AD. A recently developed research approach with Positron Emission Tomography (PET) will be used to combine neuroreceptor radiotracer studies with pharmacologic challenges to measure cholinergic modulation (Smith et al., 1996, Dewey et al., 1993). This approach is the most direct, non-invasive and quantitative method of measuring neurotransmitter activity and modulation in the living brain. These studies will measure cholinergic modulation of monoamine function (serotonin, dopamine) in the normal elderly, and in AD patients. A well- characterized pharmacologic challenge paradigm (administration of the selective muscarinic cholinegic antagonist scopolamine) will be used with PET and radiotracers for dopaminergic (D2, [1]C]- raclopride) and serotonergic (5-HT2A, [18F]-altanserin) receptors. Having performed the proposed studies, unique information will be obtained regarding cholinergic modulation of dopamine and serotonin receptor systems. These studies will provide a baseline for subsequent longitudinal follow-up of patients and for correlation with genetics and post-mortem findings (by the Alzheimer~s Disease Research Center) to determine how differences in monoaminergic responsiveness relate to AD subgroups (e.g. Lewy Body Dementia) A better understanding of the neurochemical deficits in AD may direct the development of novel treatment interventions that would improve symptomatology and perhaps stop disease progression.